Delivery devices for administering a beneficial agent to a biological environment comprising a fluid are known in the prior art. Representative examples of delivery devices are disclosed in European publications EP 25,699 and 164,241; and in U.S. Pat. Nos. 3,995,632; 4,111,202; 4,251,506; 4,612,008; 4,824,675; 4,865,598; 4,872,873; 4,876,093; 4,892,778; 4,915,949; 4,940,465; and 5,023,088.
While the prior art delivery devices usually work successfully for their intended purpose, the present inventors observed that the devices often do not function well when the dispensed formulation is combined with a carrier. When a formulation agent is dispensed from the previous devices, uncontrolled and nonuniform release of the agent is often a problem over prolonged dispensing periods, causing delivery of the agent into the environment of use in amounts and over periods of time that are not intended by the design of the prior art device, which results in erratic or incorrect dosage profiles. This has been found to be particularly true in dynamic or vigorous environments such as active, grazing animals. An additional drawback to the prior art formulations is that they attract fluid and in fact require some fluid for proper dissemination of agent into the environment and also for lubrication within the device. This presents a problem when the beneficial agent is sensitive to fluids and subject to degradation or inactivation in an aqueous environment.
Devices have been designed which contain beneficial agents in carriers, for example in U.S. Pat. No. 4,595,583. While these devices appear to solve the problem of excessive and uncontrolled erosion of the agent formulation, they have a low loading of agent within the formulation, usually of less than 40% and often lower, of 30% or less. This creates a serious problem in those instances when it is desired to have agent delivered from a single device over a period of several weeks or months, as is the case with implants and ruminal boluses. The amount of beneficial agent necessary to be included in the device for such an extended delivery period would require a very large amount of formulation at a low dosing, making the device far too large and bulky to be useful as a practical matter as an implant or ruminal bolus, for example.
One group of beneficial agents that requires special delivery technology are the ionophores. Ionophores, or ion-bearers, as reported in Ann. N.Y. Acad. Sci., Vol. 264, pp 373-86 (1985), are polyether antibiotics that modulate the physiological transport of ions across biological membranes and alter the characteristics of fermentation in the animal, resulting in favorable metabolic changes. These valuable properties of ionophores led to their use as feed additives by the livestock industry. For example, the ionophores, when fed to ruminants, resulted in an improved feed-gain ratio, as reported in Feedstuffs, pp 14, 15 and 22 (1989). In one accepted use, ionophores are fed to feedlot cattle in confinement for improved feed efficiency. In this use, the ionophore first is mixed with a finely ground nonmedicated feedstuff to produce a premix, which premix is added to an air-dry feed for feeding to cattle, including steers and heifers.
While the above described prior art use of ionophores results in improved feed efficiency, usually of from 5 to 8 percent or higher, for steers and heifers, as reported in Feedstuffs (supra), serious shortcomings accompany this use. For example, since the ionophore is mixed with feed, one shortcoming is the difficulty to ascertain the amount of ionophore ingested by the animal because of feedlot losses such as spillage and scatter. Another shortcoming resides in the absence of controlled administration of known amounts of the ionophore over time, as the composition of the feed charged with the ionophore can vary with feed millers. Also, ionophores are sensitive to moisture in the environment, which moisture can adversely affect their usefulness, and the handling and transport of feeds containing ionophores can result in the segregation of particles carrying ionophores and change the concentration level to which cattle are exposed when fed over time. Then, since ionophores usually are mixed with feeds daily, this requires extra labor that adds to the cost of the ionophore-feedstuff.
In the light of the above presentation, it will be appreciated by those versed in the dispensing art to which this invention pertains that a pressing need exists for a dosage form that can deliver a beneficial agent, such as the ionophores, to a biological environment of use in large amounts in a small volume. The pressing need exists also for a dosage form that can store a beneficial agent in a carrier and deliver the beneficial agent and carrier at a controlled rate in a substantially constant dose per unit time over a prolonged period of time essentially independent of the environment of use. It will be appreciated further by those versed in the dispensing art that if such a novel and unique dosage form is provided that can administer a beneficial agent in a carrier at a high loading and in a rate-controlled dose over time and, simultaneously, provide the beneficial effects, the dosage form would represent an advancement and valuable contribution in the agent dosage form art.